EP0827399A1 - Inhibiting photodecomposition of 3-substituted-2-oxindoles - Google Patents
Inhibiting photodecomposition of 3-substituted-2-oxindolesInfo
- Publication number
- EP0827399A1 EP0827399A1 EP95914494A EP95914494A EP0827399A1 EP 0827399 A1 EP0827399 A1 EP 0827399A1 EP 95914494 A EP95914494 A EP 95914494A EP 95914494 A EP95914494 A EP 95914494A EP 0827399 A1 EP0827399 A1 EP 0827399A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- red
- yellow
- dye
- lake
- thienyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4883—Capsule finishing, e.g. dyeing, aromatising, polishing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to the inhibition of photodecomposition of certain 3- substituted-2-oxindole-1-carboxamides of the formula
- X is H, Cl or F
- Y is H or Cl
- R is benzyl or thienyl, each optionally substituted with Cl or F.
- X is H, fluoro, chloro, brorno, (C ⁇ C alkyl, (C 3 -C 7 )cycloalkyl.
- C C 4 alkoxy, (C,-C 4 )alkylthio, trifluoromethyl, (C--C 4 )alkylsulfinyl, (C,-C 4 )alkylsulfonyl, nitro, phenyl, (C 2 -C 4 )alkanoyl, benzoyl, thenoyl, (C 1 -C 4 )alkanamido, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls;
- Y is, H, fluoro, chloro, bromo, (C,-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C,-C 4 )alkoxy, (C,-C 4 )
- R 3 and R 4 are each H, fluoro, chloro, (C,-C 4 )alkyl, (C r C 4 )alkoxy or trifluoromethyl.
- That patent also discloses that said 2-oxindole-1-carboxamides are inhibitors of cyclooxygenase and lipoxygenase, possess analgesic activity in mammals and are useful in treatment of pain and alleviation of symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
- U.S. Patent 4,556,672 discloses certain 3-acyl substituted- 2-oxindole- 1 -carboxamides of the formula
- X is H, Cl or F
- Y is H or Cl
- R is benzyl or thienyl, each optionally substituted with Cl or F; said photodecomposition resulting from light emanating from a light source which comprises introducing a light absorbing means between said compound and said light source.
- said light absorbing means is a dye selected from the group consisting of yellow #6, red #40, red #3, yellow lake #6, red lake #40 and red lake #3. in a further preferred method of this invention said light absorbing means is yellow #6.
- this invention relates to a tablet comprising a pharmaceutically active ingredient selected from a compound of the formula
- X is H, Cl or F
- Y is H or Cl
- R is benzyl or thienyl, each optionally substituted with Cl or F; said tablet being coated with a coating containing a sufficient amount of yellow dye #6, red dye #40, red dye #3, yellow lake #6, red lake #40 and red lake #3 to inhibit photodecomposition of said pharmaceutically active ingredient.
- this invention comprises a coated tablet wherein said coating contains yellow dye #6 in sufficient amount to inhibit photodecomposition of said pharmaceutically active ingredient.
- this invention comprises a capsule comprising a pharmaceutically active ingredient selected from a compound of the formula
- X is H, Cl or F
- Y is H or Cl
- R is benzyl or thienyl, each optionally substituted with Cl or F; said capsule shell containing a sufficient amount of yellow dye #6, red dye #40, red dye #3, yellow lake #6, red lake #40 and red lake #3 to inhibit photodecomposition of said pharmaceutically active ingredient.
- Light absorbing means means materials which block all or most wave lengths of light such as opaque glass or metals; or materials which absorb light with wave lengths of less than 600 nm such as ultra violet stabilizers or dyes.
- the light absorbing means may be used in packaging materials such as blister packages, sachets or bottles.
- Chemical light absorbing means such as ultraviolet stabilizers may be incorporated in packaging material including blister packages, sachets or bottles or are preferably incorporated in capsule shells or tablet coatings. Chemical light absorbing means may also be mixed directly with the active ingredient prior to tableting or placing in a capsule shell.
- the compounds protected by this invention are acidic and form base salts. All such base salts are within the scope of this invention and can be formed as taught by these patents.
- Such suitable salts include both the organic and inorganic types and include, but are not limited to, the salts formed with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides.
- bases which form such base salts include ammonia, primary amines, such as n-propylamine, n-butyiamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrroiidine and piperidine; tertiary amines, such as triethylamine, triethanolamine, N,N-dimethyianiline, N-ethylpiperidine and N-methyimorpholine; hydroxides, such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.
- primary amines such as n-propylamine, n-butyiamine, ani
- Preferred salts are those of sodium, potassium, ammonium, ethanolamine, diethanolamine and triethanolamine. Particularly preferred are the sodium salts.
- the compounds to which this invention is applicable include soivates such as the hemihydrates and monohydrates of the compounds hereinabove described.
- Red and yellow dyes have been found effective in preventing contact of light and the associated light-induced degradation of 3-substituted oxindole-1-carboxamides.
- Preferred dyes are FD&C red #40, FD&C red #3 and FD&C yellow #6. Yellow #6 is especially preferred.
- the dyes are effective in preventing light-induced degradation of 3-substituted-oxindoie-1-carboxamides when mixed with the oxindole, applied to a preformed tablet in a coating, or in a gelatin capsule containing the oxindole.
- the preferred method is the coating of tablets.
- Film coating of pharmaceutical tablets is well known in the art and is described, for example, in United States Patents 4,828,841 ; 3,981 ,948; and 3,802,896 which are hereby incorporated by reference.
- Film coating materials such as white Opadry, Opadry II, Surelease, Aquacoat and Eudragit which are suitable for formulation with the selected dye are commercially available from Colorcon, West Point, PA; FMC Corp., Philadelphia, PA; Rohm Pharma, We ' iterstadt, Germany respectively.
- Dyes may also be formulated into gelatin capsules which are then filled with the oxindole.
- the technology for preparing capsules is well known to those of ordinary skill in this art. Capsules incorporating selected dyes are available commercially from
- 3,784,684 describes the incorporation of opacifers and dyes in gelatine capsule shells.
- the amount of dye in the coating or capsule shell is not critical except that sufficient dye must be incorporated to absorb any incident light. We have found that 1.2-2.8 mgAablet of yellow #6 prevented decomposition while in capsule shells 0.28 to 0.5 mg/capsule afforded light stability.
- a typical formulation of the coated tablets of this invention may be prepared as follows:
- LC assay results for these lots are summarized in the table below. All samples were analyzed in triplicate. Assay values for the uncoated tablets were close to the intended 100 mg/g. Levels of thiophene-2-carboxylic acid, 6-chloro-1H- quinazoline-2,4-dione, thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3- dihydro 1 H-indol-3-yl ester, 6-chloro-2-hydroxy-quinazoline-4-carboxylic acid and unknown #3 for the uncoated tablets increased significantly in the light cabinet (compared to 5°C control). No significant degradation was observed for the tablet cores stored at 5°C, 30°C or 50°C.
- the above ingredients were mixed and a portion roller compacted, then milled and reblended with the remaining ingredients, lubricated and encapsulated in gelatin capsules obtained from Capsugel, a division of Warner-Lambert Company.
- a preferred lubricant is sodium laurel sulfate.
- the capsules contained FD&C yellow dye 0.2651 % of total dry weight in the capsule body and 0.1768% in the cap.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Polymerisation Methods In General (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1995/000287 WO1996033701A1 (en) | 1995-04-24 | 1995-04-24 | Inhibiting photodecomposition of 3-substituted-2-oxindoles |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0827399A1 true EP0827399A1 (en) | 1998-03-11 |
Family
ID=36997502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95914494A Ceased EP0827399A1 (en) | 1995-04-24 | 1995-04-24 | Inhibiting photodecomposition of 3-substituted-2-oxindoles |
Country Status (30)
Country | Link |
---|---|
EP (1) | EP0827399A1 (fi) |
JP (1) | JPH10506635A (fi) |
KR (1) | KR100189585B1 (fi) |
CN (1) | CN1053667C (fi) |
AP (1) | AP607A (fi) |
AR (1) | AR002728A1 (fi) |
AU (1) | AU692378B2 (fi) |
BG (1) | BG100531A (fi) |
BR (1) | BR9602024A (fi) |
CO (1) | CO4700418A1 (fi) |
FI (1) | FI973988A0 (fi) |
HR (1) | HRP960194A2 (fi) |
HU (1) | HU216544B (fi) |
IL (1) | IL117969A0 (fi) |
IS (1) | IS4339A (fi) |
MA (1) | MA23848A1 (fi) |
NO (1) | NO961622L (fi) |
NZ (1) | NZ286432A (fi) |
OA (1) | OA10286A (fi) |
PE (1) | PE34397A1 (fi) |
RO (1) | RO113305B1 (fi) |
RU (1) | RU2109510C1 (fi) |
SG (1) | SG64924A1 (fi) |
SI (1) | SI9600133A (fi) |
SK (1) | SK51296A3 (fi) |
TR (1) | TR199600300A2 (fi) |
UA (1) | UA42739C2 (fi) |
WO (1) | WO1996033701A1 (fi) |
YU (1) | YU25096A (fi) |
ZA (1) | ZA963210B (fi) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2758128C1 (ru) | 2017-12-29 | 2021-10-26 | Крафт Фудс Груп Брэндс Ллк | Улучшенная устойчивость к окислению эмульсий типа "масло в воде" при помощи натуральных стабилизаторов |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUT59592A (en) * | 1990-07-20 | 1992-06-29 | Egyt Gyogyszervegyeszeti Gyar | Process for the preparation of solid medical products |
TW438798B (en) * | 1992-10-07 | 2001-06-07 | Pfizer | 3-substituted 2-oxindole-1-carboxamide pharmaceutical compositions |
-
1995
- 1995-04-24 JP JP8532298A patent/JPH10506635A/ja active Pending
- 1995-04-24 WO PCT/IB1995/000287 patent/WO1996033701A1/en not_active Application Discontinuation
- 1995-04-24 RU RU96108120A patent/RU2109510C1/ru active
- 1995-04-24 SK SK512-96A patent/SK51296A3/sk unknown
- 1995-04-24 UA UA96041574A patent/UA42739C2/uk unknown
- 1995-04-24 EP EP95914494A patent/EP0827399A1/en not_active Ceased
-
1996
- 1996-03-07 AP APAP/P/1996/000787A patent/AP607A/en active
- 1996-03-28 AR ARP960101956A patent/AR002728A1/es unknown
- 1996-04-10 TR TR96/00300A patent/TR199600300A2/xx unknown
- 1996-04-18 IL IL11796996A patent/IL117969A0/xx unknown
- 1996-04-19 SG SG1996009306A patent/SG64924A1/en unknown
- 1996-04-19 IS IS4339A patent/IS4339A/is unknown
- 1996-04-22 PE PE1996000275A patent/PE34397A1/es not_active Application Discontinuation
- 1996-04-22 CO CO96019210A patent/CO4700418A1/es unknown
- 1996-04-22 CN CN96105084A patent/CN1053667C/zh not_active Expired - Fee Related
- 1996-04-22 RO RO96-00843A patent/RO113305B1/ro unknown
- 1996-04-23 MA MA24209A patent/MA23848A1/fr unknown
- 1996-04-23 NO NO961622A patent/NO961622L/no unknown
- 1996-04-23 KR KR1019960012356A patent/KR100189585B1/ko not_active IP Right Cessation
- 1996-04-23 HR HRPCT/IB95/00287A patent/HRP960194A2/hr not_active Application Discontinuation
- 1996-04-23 YU YU25096A patent/YU25096A/sh unknown
- 1996-04-23 NZ NZ286432A patent/NZ286432A/en unknown
- 1996-04-23 AU AU50851/96A patent/AU692378B2/en not_active Ceased
- 1996-04-23 HU HU9601057A patent/HU216544B/hu not_active IP Right Cessation
- 1996-04-23 BG BG100531A patent/BG100531A/xx unknown
- 1996-04-23 ZA ZA9603210A patent/ZA963210B/xx unknown
- 1996-04-24 SI SI9600133A patent/SI9600133A/sl not_active IP Right Cessation
- 1996-04-24 OA OA60821A patent/OA10286A/en unknown
- 1996-04-24 BR BR9602024A patent/BR9602024A/pt active Search and Examination
-
1997
- 1997-10-17 FI FI973988A patent/FI973988A0/fi unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9633701A1 * |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 19970919 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE |
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17Q | First examination report despatched |
Effective date: 20000118 |
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GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
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18R | Application refused |
Effective date: 20010405 |